Asthma is a major public health problem in particular in western countries. For example, in United States nearly 17 million Americans suffer from this disease. In the last two decades Asthma morbidity and mortality have been rising. The most common treatment of Asthma is inhaled corticosteroids which greatly reduce the symptoms of the disease. However, treatment with corticosteroids has been reported markedly to produce systemic side effects. Specifically, adrenal suppression, decreased bone metabolism, and decreased growth are of great concern when it comes to administration of corticosteroids by children. Corticosteroids also produce overall immune suppression, which results in increased susceptibility to infections. In addition, recent studies indicate that continuous daily treatment with corticosteroids had no long-term therapeutic benefit in terms of lung function because although anti-inflammatory therapy reduced the incidence of asthma symptoms in subjects with persistent asthma, it did not alter progressive lung changes or prevent recurrence of symptoms shortly after discontinuation of therapy. Alternative therapeutic approaches include leukotriene inhibitors and anti-IgE. However, those alternative medications have shown only marginal benefits.
Semaphorins are a family of membrane bound and soluble proteins classified into eight sub-classes based on their structural domains. Semaphorins mainly regulate focal adhesion assembly/disassembly and induce cytoskeletal remodeling, thus affecting cell shape, cell attachment to the extracellular matrix, cell motility, and cell migration. Although Semaphorins were originally identified as affecting axon guidance during development of the nervous system, they are now thought to fulfill diverse physiological roles including organogenesis, vascularization, angiogenesis, neuronal apoptosis, and neoplastic transformation. Additionally, recent studies pointed to the involvement of Neuropilin-1 (a receptor for Semaphorin 3) and certain Semaphorins in the regulation of the immune system, and thus these Semaphorins are denoted “immune Semaphorins”.
The seven class-3 Semaphorins (Semaphorin 3s), designated by the letters A-G, are the only 5vertebrate secreted Semaphorins. Neuropilins (Nrps) and the type A/D family Plexins (Plexin-A1, -A2, and -A3, and Plexin-D1) act as receptors for Semaphorin 3. Each Semaphorin 3 family member shows distinct binding preference for Nrps. Each Sema3-Nrp complex associates with specific plexins to mediate downstream signaling. Most membrane-bound vertebrate Semaphorins directly bind plexins, while class-3 Semaphorins require Neuropilins as obligate co-receptors.
Semaphorin 3A (Sema3A), a class-3 secreted member of the Semaphorin family, has been established as an axonal guidance factor during development. Interestingly, several lines of evidence suggest that Sema3A also affects immune cell functions. Sema3A has been shown to be expressed by activated T cells and inhibit T cell proliferation and cytokine secretion (Catalano, A et al, 2006, Blood 107: 3321-3329; Lepelletier, Y. et al., 2006, Eur. J. Immunol. 36: 1782-1793). Moreover, the expression of Sema3A, Neuropilin 1 (NP-1), Neuropilin 2 (NP-2), and Plexins was found to be increased on differentiating macrophages and on activated T cells (Ji J D et al., 2009, Human Immunol., 70(4): 211-7). Additionally, Neuropilin-1 expression on regulatory T cells has been shown to enhance interactions with immature dendritic cells (DCs) during antigen recognition, resulting in higher sensitivity to limiting amounts of antigen.
One study has shown that overexpression of Sema3A in a mouse model of collagen-induced arthritis resulted in reduced incidence, disease severity, and articular inflammation. Moreover, in line with results in arthritic mice, the study showed a defective Sema3A expression in CD4+ T cells derived from patients with rheumatoid arthritis (Catalano A. et al., 2010, J. Immunol., 185: 6373-83).
In another study, kidney biopsies from lupus glomerulonephritis (LGN) patients showed stronger staining with anti-NP-1, anti-Semaphorin 3A and anti-Semaphorin 4A antibodies as compared with either normal biopsies or biopsies from patients with primary nephropathy and proteinuria (Vadasz Z. et al., 2011, Lupus, 20:1466-1473). A subsequent study has shown that Sema 3A serum levels in Systemic Lupus Erythematosus (SLE) patients are significantly lower than in healthy individuals (Vadasz Z. et al, 2012, Arthritis Research & Therapy, 14:R146).
International patent application, publication No. WO2014/199364 to the inventors of the present invention, relates to Semaphorin 3A and use thereof in treatment and prognosis of Systemic Lupus Erythematosus (SLE).
U.S. Application Publication No. 2012/0251539 discloses a method of treating an immune-related disorder in a subject, comprising administering to the subject an effective amount of a Sema3A inhibitor, resulting in reduced Sema3A activity in the subject.
In yet another study, it has been shown that administration of Sema3A alleviates sneezing and nasal rubbing in a murine model of Allergic Rhinitis (Sawaki H. et al., 2011, J. Pharmacol. Sci., 117(1): 34-44).
There is an unmet need in the art, for safe and effective approaches to treat asthma. There is also a need for reliable and accurate biomarkers with which treatment efficacy and disease condition and/or severity can be assessed.